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Purpose It is purported that caffeine, an autonomic stimulant, affects visual performance. This study sought to assess whether caffeine intake was associated with changes in pupil size and/or amplitude of accommodation. Patients and methods A double-masked, crossover study was conducted in 50 healthy subjects of age range 19 to 25 years. Subjects were randomized to treatments such that subjects consumed either 250 mg caffeine drink or vehicle on separate days. Amplitude of accommodation was measured by the push-up technique, and pupil size using a millimeter ruler fixed to a slit lamp biomicroscope in dim illumination (5 lux). Amplitude of accommodation and pupil size were taken at baseline, and at 30, 60 and 90 min time points post treatment. Repeated measures one-way ANOVA and paired t- test were used in analyzing data. Results Amplitude of accommodation and pupil size after caffeine intake were significantly greater than vehicle ( P <0.001) at each time point. Consumption of the caffeine beverage was associated with significant increases in amplitude of accommodation and pupil size with time ( P <0.001). Amplitude of accommodation rose from 12.4 (±2.2 D) at baseline to 15.8(±2.6 D) at 90 min. Similarly, pupil size increased from 3.4 (±0.4 mm) at baseline to 4.5 (±0.72 mm) at 90 min. Consumption of vehicle was not associated with increase in amplitude of accommodation or pupil size with time. Conclusion Pupil size and accommodation are affected after ingestion of caffeine. This study suggests caffeine may have some influence on visual functions.

Variation in the third retinal photoreceptor For many years, it was thought that rods and cones were the only light-detecting cells in the mammalian retina, but about 20 years ago a third photoreceptor was identified, the intrinsically photosensitive retinal ganglion cells (ipRGCs). Expressing the photo-pigment melanopsin, these cells assist in the regulation of circadian photoentrainment and help to drive the pupillary light reflex. Chen et al . now show that these two functions are associated with distinct subpopulations of ipRGCs, defined by specific molecular factors and acting in parallel. Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and regulate a wide array of light-dependent physiological processes 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . Genetic ablation of ipRGCs eliminates circadian photoentrainment and severely disrupts the pupillary light reflex (PLR) 12 , 13 . Here we show that ipRGCs consist of distinct subpopulations that differentially express the Brn3b transcription factor, and can be functionally distinguished. Brn3b-negative M1 ipRGCs innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, whereas Brn3b-positive ipRGCs innervate all other known brain targets, including the olivary pretectal nucleus. Consistent with these innervation patterns, selective ablation of Brn3b-positive ipRGCs severely disrupts the PLR, but does not impair circadian photoentrainment. Thus, we find that molecularly distinct subpopulations of M1 ipRGCs, which are morphologically and electrophysiologically similar, innervate different brain regions to execute specific light-induced functions.

Background The pupillary response to tetanic electrical stimulation reflects the balance between nociceptive stimulation and analgesia. Although pupillary pain index (PPI) was utilized to predict postoperative pain, it depended on tetanic stimulation and was complex. We aim to describe the potential relationship between PD in the presence of surgical stimulation and pain levels after awakening. Methods According to the Verbal Rating Scale (VRS) score after extubation, the patients were divided into painless group (VRS = 0) and pain group (VRS ≥ 1). Pupillary diameter (PD) and pupillary light reflex velocity (PLRV) were compared between two groups when patients entered the operating room (T 1 ), before incision (T 2 ), 10 s after incision (T 3 ), 30 s after incision (T 4 ), 1 h after incision (T 5 ), at the end of surgery (T 6 ), shortly after extubation (T 7 ), and when patients expressed pain clearly (T 8 ). The magnitude of PD change (ΔPD) compared to the baseline value after anesthesia induction (T 2 ) was calculated. The correlations between pupillary parameters and pain after awakening were calculated. Results Patients with VRS ≥ 1 had greater PD than painless patients at T 3-7 ( P  = 0.04, 0.04, 0.003, <0.001, <0.001), and it was positively correlated with VRS score after awakening at T 4-7 ( r  = 0.188, 0.217, 0.684, 0.721). The ability of T 6 ΔPD to predict VRS ≥ 1 was strong [threshold: 20.53%, area under the curve (AUC): 0.93, 95% confidence interval (CI): 0.89–0.97 ]. Conclusion Our study indicates that PD is a useful index to direct the individualized analgesics used during operation, to better avoid the occurrence of pain during the postoperative emergence period. Trial registration This study was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR2000040908, registration date: 15/12/2020).

Physiological effects of light exposure in humans are diverse. Among them, the circadian rhythm phase shift effect in order to maintain a 24-h cycle of the biological clock is referred to as non-visual effects of light collectively with melatonin suppression and pupillary light reflex. The non-visual effects of light may differ depending on age, and clarifying age-related differences in the non-visual effects of light is important for providing appropriate light environments for people of different ages. Therefore, in various research fields, including physiological anthropology, many studies on the effects of age on non-visual functions have been carried out in older people, children and adolescents by comparing the effects with young adults. However, whether the non-visual effects of light vary depending on age and, if so, what factors contribute to the differences have remained unclear. In this review, results of past and recent studies on age-related differences in the non-visual effects of light are presented and discussed in order to provide clues for answering the question of whether non-visual effects of light actually vary depending on age. Some studies, especially studies focusing on older people, have shown age-related differences in non-visual functions including differences in melatonin suppression, circadian phase shift and pupillary light reflex, while other studies have shown no differences. Studies showing age-related differences in the non-visual effects of light have suspected senile constriction and crystalline lens opacity as factors contributing to the differences, while studies showing no age-related differences have suspected the presence of a compensatory mechanism. Some studies in children and adolescents have shown that children’s non-visual functions may be highly sensitive to light, but the studies comparing with other age groups seem to have been limited. In order to study age-related differences in non-visual effects in detail, comparative studies should be conducted using subjects having a wide range of ages and with as much control as possible for intensity, wavelength component, duration, circadian timing, illumination method of light exposure, and other factors (mydriasis or non-mydriasis, cataracts or not in the older adults, etc.).

PurposeOut-of-hospital cardiac arrest (OHCA) survivors face significant risks of complications and death from hypoxic–ischemic brain injury leading to withdrawal of life-sustaining treatment (WLST). Accurate multimodal neuroprognostication, including automated pupillometry, is essential to avoid inappropriate WLST. However, inconsistent study results hinder standardized threshold recommendations. We aimed to validate proposed pupillometry thresholds with no false predictions of unfavorable outcomes in comatose OHCA survivors.MethodsIn the multi-center BOX-trial, quantitative measurements of automated pupillometry (quantitatively assessed pupillary light reflex [qPLR] and Neurological Pupil index [NPi]) were obtained at admission (0 h) and after 24, 48, and 72 h in comatose patients resuscitated from OHCA. We aimed to validate qPLR < 4% and NPi ≤ 2, predicting unfavorable neurological conditions defined as Cerebral Performance Category 3–5 at follow-up. Combined with 48-h neuron-specific enolase (NSE) > 60 μg/L, pupillometry was evaluated for multimodal neuroprognostication in comatose patients with Glasgow Motor Score (M) ≤ 3 at ≥ 72 h.ResultsFrom March 2017 to December 2021, we consecutively enrolled 710 OHCA survivors (mean age: 63 ± 14 years; 82% males), and 266 (37%) patients had unfavorable neurological outcomes. An NPi ≤ 2 predicted outcome with 0% false-positive rate (FPR) at all time points (0–72 h), and qPLR < 4% at 24–72 h. In patients with M ≤ 3 at ≥ 72 h, pupillometry thresholds significantly increased the sensitivity of NSE, from 42% (35–51%) to 55% (47–63%) for qPLR and 50% (42–58%) for NPi, maintaining 0% (0–0%) FPR.ConclusionQuantitative pupillometry thresholds predict unfavorable neurological outcomes in comatose OHCA survivors and increase the sensitivity of NSE in a multimodal approach at ≥ 72 h.

Purpose To compare the chromatic pupillary light responses (PLR) in healthy subjects with those from patients with diseases of the outer or inner retina under various stimulus conditions, and to ascertain the parameters required to optimally distinguish between disease and control groups. Methods Fifteen patients with retinitis pigmentosa (RP), 19 patients with optic nerve disease (ON), and 16 healthy subjects were enrolled in this prospective study. ON included optic neuritis (NNO) and non-arteritic anterior ischemic optic neuropathy (NAION). For each subject, the PLR was recorded, to red, yellow, green, and blue stimuli for durations of 4 and 12 s, and for stimulus intensities of 4 lx and 28 lx. Results Comparison between control and RP or ON patient results showed that responses after stimulus onset were significantly different for most stimulus conditions, but the post-stimulus amplitudes at 3 s and 7 s after light extinction were not. On the other hand, the difference between the ON and RP groups was significant only for post-stimuli time-points and only for blue stimuli. Differences between responses to blue and red were significantly different, predominantly at post stimulus time-points. A ROC analysis revealed that the maximal constriction amplitudes to a 4 lx, 4 s yellow stimulus are significantly different in ON vs RP patients, and the responses to a 4 s, 28 lx blue stimulus at 7 s post-stimulus are significantly different in controls vs ON vs RP patients with a high specificity. Conclusions Pupillary light responses to blue light in healthy, RP, and ON subjects are significantly different from one another. The optimal stimuli for future protocols was found to be a 4 s blue stimulus at 28 lx, and a 4 s yellow stimulus at 4 lx.

Retinal ganglion cells (RGCs) drive diverse, light-evoked behaviors that range from conscious visual perception to subconscious, non–image-forming behaviors. It is thought that RGCs primarily drive these functions through the release of the excitatory neurotransmitter glutamate. We identified a subset of melanopsin-expressing intrinsically photosensitive RGCs (ipRGCs) in mice that release the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at non–image-forming brain targets. GABA release from ipRGCs dampened the sensitivity of both the pupillary light reflex and circadian photoentrainment, thereby shifting the dynamic range of these behaviors to higher light levels. Our results identify an inhibitory RGC population in the retina and provide a circuit-level mechanism that contributes to the relative insensitivity of non–image-forming behaviors at low light levels.

The size of the human pupil increases as a function of mental effort. However, this response is slow, and therefore its use is thought to be limited to measurements of slow tasks or tasks in which meaningful events are temporally well separated. Here we show that high-temporal-resolution tracking of attention and cognitive processes can be obtained from the slow pupillary response. Using automated dilation deconvolution, we isolated and tracked the dynamics of attention in a fast-paced temporal attention task, allowing us to uncover the amount of mental activity that is critical for conscious perception of relevant stimuli. We thus found evidence for specific temporal expectancy effects in attention that have eluded detection using neuroimaging methods such as EEG. Combining this approach with other neuroimaging techniques can open many research opportunities to study the temporal dynamics of the mind’s inner eye in great detail.

Background In the mammalian retina, intrinsically-photosensitive retinal ganglion cells (ipRGC) detect light and integrate signals from rods and cones to drive multiple non-visual functions including circadian entrainment and the pupillary light response (PLR). Non-visual photoreception and consequently non-visual sensitivity to light may change across child development. The PLR represents a quick and reliable method for examining non-visual responses to light in children. The purpose of this study was to assess differences in the PLRs to blue and red stimuli, measured one hour prior to bedtime, between children and adolescents. Methods Forty healthy participants (8–9 years, n  = 21; 15–16 years, n  = 19) completed a PLR assessment 1 h before their habitual bedtime. After a 1 h dim-light adaptation period (< 1 lx), baseline pupil diameter was measured in darkness for 30 s, followed by a 10 s exposure to 3.0 × 10 13 photons/cm 2 /s of either red (627 nm) or blue (459 nm) light, and a 40 s recovery in darkness to assess pupillary re-dilation. Subsequently, participants underwent 7 min of dim-light re-adaptation followed by an exposure to the other light condition. Lights were counterbalanced across participants. Results Across both age groups, maximum pupil constriction was significantly greater ( p  < 0.001, η p 2  = 0.48) and more sustained ( p  < 0.001, η p 2  = 0.41) during exposure to blue compared to red light. For adolescents, the post-illumination pupillary response (PIPR), a hallmark of melanopsin function, was larger after blue compared with red light ( p  = 0.02, d = 0.60). This difference was not observed in children. Across light exposures, children had larger phasic ( p  < 0.01, η p 2  = 0.20) and maximal ( p  < 0.01, η p 2  = 0.22) pupil constrictions compared to adolescents. Conclusions Blue light elicited a greater and more sustained pupillary response than red light in children and adolescents. However, the overall amplitude of the rod/cone-driven phasic response was greater in children than in adolescents. Our findings using the PLR highlight a higher sensitivity to evening light in children compared to adolescents, and continued maturation of the human non-visual photoreception/system throughout development.

Background Sedation and therapeutic hypothermia (TH) delay neurological responses and might reduce the accuracy of clinical examination to predict outcome after cardiac arrest (CA). We examined the accuracy of quantitative pupillary light reactivity (PLR), using an automated infrared pupillometry, to predict outcome of post-CA coma in comparison to standard PLR, EEG, and somato-sensory evoked potentials (SSEP). Methods We prospectively studied over a 1-year period (June 2012–June 2013) 50 consecutive comatose CA patients treated with TH (33 °C, 24 h). Quantitative PLR (expressed as the % of pupillary response to a calibrated light stimulus) and standard PLR were measured at day 1 (TH and sedation; on average 16 h after CA) and day 2 (normothermia, off sedation: on average 46 h after CA). Neurological outcome was assessed at 90 days with Cerebral Performance Categories (CPC), dichotomized as good (CPC 1–2) versus poor (CPC 3–5). Predictive performance was analyzed using area under the ROC curves (AUC). Results Patients with good outcome [ n  = 23 (46 %)] had higher quantitative PLR than those with poor outcome [ n  = 27; 16 (range 9–23) vs. 10 (1–30) % at day 1, and 20 (13–39) vs. 11 (1–55) % at day 2, both p  < 0.001]. Best cut-off for outcome prediction of quantitative PLR was <13 %. The AUC to predict poor outcome was higher for quantitative than for standard PLR at both time points (day 1, 0.79 vs. 0.56, p  = 0.005; day 2, 0.81 vs. 0.64, p  = 0.006). Prognostic accuracy of quantitative PLR was comparable to that of EEG and SSEP (0.81 vs. 0.80 and 0.73, respectively, both p  > 0.20). Conclusions Quantitative PLR is more accurate than standard PLR in predicting outcome of post-anoxic coma, irrespective of temperature and sedation, and has comparable prognostic accuracy than EEG and SSEP.